Twisted: Escape of epitope-edited healthy cells from immune attack

Hematopoietic stem and progenitor cell-derived neoplasia is challenging to target by cell surface-directed immunotherapy due to lack of tumor cell-specific antigen identification. Marone et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20231235) provide a solution by target-epitope resistance editing in healthy hematopoietic stem cells

Automobilantriebe im Wandel

Der Automobilantrieb ist eng mit dem globalen wirtschaftlichen Erfolg und dessen Wachstum verbunden. Nie zuvor konnten größere Distanzen von so vielen Individuen und Gütern in so kurzer Zeit zurückgelegt werden. Aufgrund der aktuellen wirtschaftlichen und ökologischen Lage sind die Automobilbauer gefordert Antriebe zu entwickeln, die möglichst geringe Emissionen mit einem maximalen Wirkungsgrad und dennoch großen Reichweiten ermöglichen. Dabei verfügt der Automobilmarkt über eine große Vielfalt und aufgrund der zunehmenden Anforderungen und regional abhängigen Randbedingungen (Gesetze, Emissionsanforderungen, etc.), sowie den Interessenkonflikten bei den Herstellern, über eine hohe Komplexität. Auch der zukünftige Endverbraucher hat Anforderungen an sein Fahrzeug. Wie groß ist die Reichweite eines Elektrofahrzeugs? Wie kann diese bei Bedarf gesteigert werden? Sind diese Antriebe wirklich effizient? Um diese Fragen beantworten zu können, muss der aktuelle Stand der Technik näher beleuchtet werden, so dass die teilweise geringen Unterschiede, gerade bei Hybridsystemen, nachvollzogen werden können und um die individuellen Vorteile greifbarer zu machen. Letztendlich wird klar, dass sich der Antrieb verändern wird und trotz, oder gerade wegen der zunehmenden Elektrifizierung und Hybridisierung, wird dennoch der Verbrennungsmotor die dominante Antriebsquelle über einen längeren Zeitraum bleiben

Clonal Type I Interferon–producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations

Because of different cytokine responsiveness, surface receptor, and transcription factor expression, human CD11c− natural type I interferon–producing cells (IPCs) and CD11c+ dendritic cells were thought to derive through lymphoid and myeloid hematopoietic developmental pathways, respectively. To directly test this hypothesis, we used an in vitro assay allowing simultaneous IPC, dendritic cell, and B cell development and we tested lymphoid and myeloid committed hematopoietic progenitor cells for their developmental capacity. Lymphoid and common myeloid and granulocyte/macrophage progenitors were capable of developing into both functional IPCs, expressing gene transcripts thought to be associated with lymphoid lineage development, and into dendritic cells. However, clonal progenitors for both populations were about fivefold more frequent within myeloid committed progenitor cells. Thus, in humans as in mice, natural IPC and dendritic cell development robustly segregates with myeloid differentiation. This would fit with natural interferon type I–producing cell and dendritic cell activity in innate immunity, the evolutionary older arm of the cellular immune system

Addition of romiplostim to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays

Humanized mice: are we there yet?

Animal models have been instrumental in increasing the understanding of human physiology, particularly immunity. However, these animal models have been limited by practical considerations and genetic diversity. The creation of humanized mice that carry partial or complete human physiological systems may help overcome these obstacles. The National Institute of Allergy and Infectious Diseases convened a workshop on humanized mouse models for immunity in Bethesda, MD, on June 13–14, 2005, during which researchers discussed the benefits and limitations of existing animal models and offered insights into the development of future humanized mouse models

Identifying future district heating potentials in Germany: a study using empirical insights and distribution cost analysis

District heating will play an important role in the transition towards climate-neutral heating. Various studies on modelling the energy system show that district heating and the related expansion of the networks can have different levels of importance. A main reason is that the costs for distribution grid expansion are not well or not at all considered and empirical evidence for a threshold for cost-effective distribution costs is missing in such studies. In this paper, we aim to improve empirical evidence allowing to improve the representation of future district heating expansion in energy systems models. For that, the current status of district heating is analysed in high spatial resolution for Germany. The results show that with the currently accepted average costs, a large range of the possible future market share of district heating for buildings between 17 - 52% is possible by 2050, with the parameters of the connection rate and the renovation rate of the building stock. We conclude that the district heating share could be increased by the factor of 2 to 5 in the future, proving the importance of climate-neutral district heating in the transition

Nutrient mass balance of the seagrass Posidonia oceanica: the importance of nutrient retranslocation

The seasonal nutrient mass balance of the dominant seagrass of the Mediterranean, Posidonia oceanica (L.) Delde, was evaluated in NE Spain in order to test the hypothesis that the effect of seasonal nutrient imbalance can be reduced by the reutilization of internal nutrient pools. To this end we investigated the seasonal and age-dependent variability of nitrogen and phosphorus concentration of the leaves, inferring from these data values of seasonal nitrogen and phosphorus incorporation, uptake, losses and retranslocation. Incorporation of nitrogen and phosphorus in leaves peaked in June and was lowest in September, thus following the seasonal growth pattern of the plant. Retranslocation of nitrogen and phosphorus was high from May to September and close to zero during the rest of the year. Losses of nitrogen and phosphorus were highest at the end of summer, associated with the major biomass losses. Nitrogen uptake by leaves reached maximum values in winter and was lowest during August-September, while phosphorus uptake was highest in spring and lowest in August-September. On an annual basis nitrogen and phosphorus uptake accounted for 60 and 41 % of the total nutrient incorporation, respectively, while retranslocation of nutrients from old tissues accounted for the remaining 40 and 59%. Although roots and rhizomes function as sources of nutrients at the beginning of the summer, their contribution to the seasonal nutrient budget seemed to be minor.This work was supported by grant STEP-0063-C of the ECC.Peer reviewe

Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-committed Progenitors to Flt3+ Dendritic Cells In Vivo

Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice. The exact developmental stages at which hematopoietic progenitors express Flt3, are responsive to its ligand, and subsequently develop to DCs, are not known. Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3. The receptor is down-regulated once definitive B cell, T cell, and megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable on other steady state hematopoietic cell populations. Upon in vivo Flt3 ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny DCs are expanded, whereas Flt3− downstream progenitors are not, or are only slightly increased. Transplantation of common lymphoid and common myeloid progenitors and subsequent Flt3L injection increases progeny DCs of both precursor populations. These findings provide a definitive map of Flt3 expression in the hematopoietic hierarchy and directly demonstrate that Flt3L can drive DC development along both the lymphoid and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs

Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon–producing and dendritic cell development

Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon–producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3+ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3− (Flt3−Lin−IL-7Rα−Thy1.1−c-Kit+) and Flt3+ (Flt3+Lin−IL-7Rα−Thy1.1−c-Kit+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3− megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development–affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3− MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3– and Flt3-PU.1–mediated IPC and DC differentiation program in Flt3+ hematopoietic progenitor cells